Psychostimulants, including methylphenidate (MPH), are currently the most effective treatment for attention-deficit hyperactivity disorder (ADHD). These drugs ameliorate a variety of deficits in cognitive/behavioral processes dependent on the prefrontal cortex (PFC) seen in ADHD patients, including behavioral inhibition/impulsivity regulation, working memory, and attention. Importantly, these actions are not limited to ADHD, having been well documented in normal humans and animals. Despite their clinical effectiveness, concern over abuse potential raises concerns over the widespread use of these drugs, particularly in children. A better understanding of the neurobiology of the cognition-enhancing actions of psychostimulants will likely facilitate the discovery of novel drug treatments for ADHD and other conditions associated with PFC dysfunction. Additionally, such information will increase our understanding of the neurobiology of higher cognitive processes. Systemic administration of MPH and all other approved ADHD medications improves higher cognitive function of rats as measured in a delayed spatial alternation test of working memory. Recently, the applicant demonstrated that psychostimulant action within the PFC, but not dorsomedial striatum, is sufficient to improve working memory. The first aim of the proposed research will investigate the receptor mechanisms within the PFC involved in the cognition enhancing actions of psychostimulants. In particular, these studies will determine the degree to which specific catecholamine receptors within the PFC are necessary for the cognition-enhancing actions of intra-PFC and systemically-administered MPH. The second aim of the proposed research will determine the degree to which the cognition-enhancing actions of MPH are associated with alterations in frontostriatal neuronal activity. These latter studies will utilize a conditional intensity-general linear model to analyze drug-induced alterations in frontostriatal neural discharge in animals engaged in a delayed response tasks of working memory. In particular, this aim will determine the degree to which cognition-enhancing doses of MPH increase recurrent activation of PFC and dorsomedial striatal neurons during and outside the delay interval of this task. This proposal has two primary training goals. First, it will allow the appliant to further develop expertise in the pharmacology and neurocircuitry of cognitive enhancers. Second, it will provide training in electrophysiological and statistical modeling methods to better understand the neural bases of higher cognitive function and drug-induced alterations in cognitive function. These studies will greatly aid the applicant in the progression towards becoming an independent scientist studying the neural circuitry/pharmacology of higher cognitive function. PUBLIC HEALTH RELEVANCE: Attention deficit hyperactivity disorder (ADHD) is a cognitive/behavioral syndrome afflicting 3-8% of the population and associated with an increased risk in a number of domains including academic, social and health-related. While psychostimulants are currently the most effective treatment for this disorder, abuse potential raises concern over the widespread use of these drugs, particularly in children. This research aims to increase our understanding of the neurobiology of the cognition-enhancing actions of psychostimulants and facilitate the discovery of novel drug treatments for ADHD and other conditions associated with PFC dysfunction.